老年冠心病治疗策略的演变课件

1、老年冠心病治疗策略的演变The Strategic Changes of ElderlyCoronary Heart Disease Treatment陈可冀 Chen Ke-ji 徐浩 Xu Hao中国中医科学院西苑医院心血管病中心卫生部中日友好医院全国中西医结合心血管病中心 2008-05-23 1老年冠心病临床特点Clinical Features of Elderly CHD严重心绞痛多/多支血管病变多/复杂病变多/弥漫和钙化病变多/陈旧心梗多/左室功能受累多/并存病多/无症状多/合并糖尿病多/严重心律失常多/病死率高 (高龄者三支病变60%-TIME/APPROACH 试验) (75

2、岁CHD发病率:男18.6%,女6.1%) (PCI,出血并发症16.6%)治疗目的:缓解症状/改善功能/提高生活质量2冠心病治疗观念的改变Novel Changes in Concept of Elderly CHDTreatment Luminal stenosis to vulnerable plaque formation 从重视管腔狭窄到易损斑块 Lipid deposit to inflammatory response 从注意脂质沉积到炎症反应 Vulnerable plaque to vulnerable patient 从重视易损斑块到易损病人Epicardial vesse

3、l open to myocardial perfusion从注意心外膜冠脉开通到心肌组织水平灌注Outshine others to trio 从一枝独秀到三驾马车Single RF control to multi-RF intervention 从单一危险因素控制到多个危险因素联合干预Standardized treatment to individualized therapy 从注重规范化治疗到个体化治疗3Luminal Stenosis管腔狭窄Vulnerable Plaque易损斑块冠心病治疗观念改变之一First Change in Concept of CHD Treatme

4、nt4Degree of Coronary Stenosis冠脉狭窄程度Risk of CHD冠心病严重度动脉粥样硬化的传统观念Traditional Concept of Atherosclerosis?5降脂疗法降低心脏事件但并不改变管腔狭窄Lipid-lowering Therapies Decrease Cardiac Events but Not StenosisTrialCholesterol Decrease, %Cardiac Event Decrease, %Change in Stenosis, %FATS2380-1.1 3.7STARS1469-0.53.6STARS2

5、389-1.5 4.0SCRIP16390.32.5PLAC 119740.69Levine GN, Keaney JF Jr, Vita JA. Cholesterol reduction in cardiovascular disease: clinical benefits and possible mechanisms. N Engl J Med. 1995;332:512-521.Philbin EF, Pearson TA. How does lipid-lowering therapy rapidly reduce ischemic events? J Myocard Ische

6、mia. 1994;6:13-18. Pitt B, Mancini GBJ, Ellis SG, Rosman HS, Park J-S, McGovern ME, for the PLAC I investigators. Pravastatin limitation of atherosclerosis in the coronary arteries (PLAC I): reduction in atherosclerosis progression and clinical events. J Am Coll Cardiol. 1995;26:1133-11397Coronary A

7、rtery Stenosis And Cardiac Events冠脉狭窄与心脏事件Plaque volume or severity of coronary artery stenosis may not be the key factor for inducing cardiac events.提示:冠脉狭窄并非心血管事件关键原因810多方位策略演变 Many sided strategic changes诊断进步：由以CAG为主导，到重视斑块检测技术的发展如IVUS、OCT；基础研究方向：逐渐以稳定易损斑块以及减少斑块破裂后血栓形成为方向；二级预防重点：也将由治疗冠脉狭窄转为易损斑块的干

8、预。 60 micron CapLesion11CHD develops in 2030 years 冠心病慢性病程Plaque rupture occurs in 23 hrs 斑块破裂快过程DyslipidemiaAtherosclerosisPlaque formationCHD ACSHeart failure LV dysfunction心脏事件的发生 Progression of Cardiac Events AMI LV reconstruction12COURAGE临床试验 Boden WE, et al. Optimal Medical Therapy with or wit

9、hout PCI for Stable coronary Disease (NEJM.356:1503-1516;April 12,2007) 14COURAGE 研究设计Study design of COURAGE trial加PCI 组不加PCI组死亡率/ MACE/ACS 2287例稳定型心绞痛患者( 他汀类, 抗血小板, ACEI/ARB, -受体阻滞剂)随机化随访 2.5-7 Y15随访心绞痛缓解率Freedom from Angina During Long-Term Follow-upCharacteristicPCI + OMT OMT CLINICALAngina free

10、 no. Baseline12%13%1 Yr66%58%3 Yr72%67%5 Yr74% 72%The comparison between the PCI group and the medical-therapy group was significant at 1 year ( P0.001) and 3 years (P=0.02) but not at baseline or 5 years. 17震撼全球心血管病学界Grobal impact on cardiological field慢性稳定性冠心病/临界狭窄病变者:现代药物治疗效果理想/病人依从性好 COURAGE tri

11、al: 医生应该有信心面对这些病人 保护病人效果和利益的最大化 在病人身上做有证据的治疗 中西医结合应受理解和提倡18两组总生存率Overall SurvivalNumber at RiskMedical Therapy 1138 1073 1029917 717 468 302 38PCI 1149 1094 1051929 733 488 312 44Years01234560.00.50.60.70.80.91.0PCI + OMTOMT7Hazard ratio: 0.8795% CI (0.65-1.16)P = 0.3819稳定易损斑块的重要作用Stabilization of V

12、ulnerable PlaquesThe vascular pathophysiological research has focused on stabilizing the vulnerable plaque and inhibiting thrombosis after plaque rupture. The secondary prevention of CHD also focused on intervention of the vulnerable plaque in addition to treating luminal stenosis of coronary artery

13、. 防治重点应是易损斑块+狭窄问题Kullo IJ, Edwards WD, Schwartz RS. Vulnerable plaque: pathobiology and clinical implications. Ann Intern Med 1998; 129(12):1050-60. Ozer K, Cilingiroglu M. Vulnerable plaque: definition, detection, treatment, and future implications. Curr Atheroscler Rep. 2005; 7(2):121-620Lipid Dep

14、osit脂质沉积Inflammatory Reaction炎症反应冠心病治疗观念改变之二Second Change in Concept of CHD Treatment 21逾百年之脂质沉积学说Lipid Deposition Theory“Lipid deposition theory” of atherosclerosis has been put forward for 150 years based on the causal relationship between hyperlipidemia and AS. 高脂血症与动脉粥样硬化关系This theory holds that

15、 lipid deposition on the artery wall leads to the AS plaques, and it has been dominated the pathogenesis of AS for a long time. Steinberg D, Joseph L，Witztum JL. Lipoproteins and atherogenesis: Current concepts. JAMA 1990; 264(23):3047-3052. 22In recent years, AS was shown to have the basic manifest

16、ation of inflammation 炎症反应的基本表现DegenerationExudation ProliferationThe cell-cell interaction is similar to other chronic inflammation diseases such as rheumatoid arthritis, chronic pancreatitis and hepatic cirrhosis. AS was no longer regarded as a simple disease of lipid deposition in the vessel wall

17、, but also an advanced inflammatory reaction. In AS plaque of human, there was also evidence of several pathogens 病原Chlamydia pneumoniaeCytomegalovirusHerpes virusHelicobacter pylori动脉粥样硬化炎症学说Inflammation Theory24动脉粥样硬化炎症学说Inflammation TheoryIn 1999, a century later, Ross declared that AS is one of

18、chronic inflammatory disease, based on his injury reaction theory.损伤反应理论的提出 (Ross,1999)25Inflammatory BiomarkersAS炎症生物学标志物Inflammatory Biomarkers白介素-6反应蛋白单核细胞趋化因子-1血清淀粉样蛋白肿瘤坏死因子白介素-18白介素-10 细胞间黏附分子血管细胞黏附分子E-选择素血管性假血友病因子髓过氧化物酶磷脂酶血浆脂蛋白相关性磷脂酶血管内皮生长因子胎盘生长因子肝细胞生长因子基质金属蛋白酶1，2，9妊娠相关血浆蛋白-ACD40配体P-选择素27AS炎症生

19、物学标志物Hs-CRPC-Reactive Protein in CVDElevated hs-CRP levels in healthy populations predict vascular events such as MI and stroke as well as the development of diabetes. Hs-CRP is a useful biomarker in risk prediction and treatment outcome assessment.Hs-CRP was also implicated directly in atherogenesi

20、s. CRP has been found in human atherosclerotic plaque and shown to cause endothelial cell dysfunction, oxidant stress and intimal hypertrophy in experimental models.It could also be a potential target of AS treatment and prevention. 高敏C反应蛋白增高Wilson AM, Ryan MC, Boyle AJ. The novel role of C-reactive

21、 protein in cardiovascular disease: risk marker or pathogen. Int J Cardiol. 2006; 106(3):291-7. 28基于几种生化标记物的心血管事件相对风险01.02.04.06.0Lipoprotein(a)LDLCHomocysteineTCApolipoprotein BTC:HDLChs-CRPhs-CRP + TC:HDLCRelative Risk of Future CV EventsCV, cardiovascular; TC, total cholesterol; LDLC, low-density

22、 lipoprotein cholesterol; HDL-C, high-density lipo-protein cholesterol; CRP, C-reative protein; hs-CRP, high-sensitivity C-reactive protein; TC, total cholesterol.Adapted from Rifai N, et al. Clin Chem. 2001;47:28-30.29hs-CRP (mg/L)他汀治疗6周对hs-CRP水平的影响The influence of Statins on hs-CRP levelJialal I e

23、t al. Circulation 2001;103:1933-1935.6543210Baseline*Prava(40 mg/d)Simva(20 mg/d)Atorva(10 mg/d)*p0.025 vs. Baseline30ENHANCE试验的启示Enlightenment from ENHANCE trialKastelein,JJ.NEJM.April 3,2008;P.1431-144331冠心病治疗策略的更新Therapeutic Strategies for CHDEvidence based approach Despite regulating blood lipid

24、 metabolism, statins should be recommended in its anti-inflammation and other protective effects on cardiovascular diseases. 推荐他汀药物的应用Anti-inflammation - several strategies that interfere with inflammation are in progress. 一些干予炎症治疗策略在发展中Ozer K, Cilingiroglu M. Vulnerable plaque: definition, detectio

25、n, treatment, and future implications. Curr Atheroscler Rep. 2005; 7(2):121-6. 32Vulnerable Plaque易损斑块Vulnerable Patient易损病人冠心病治疗观念改变之三Third Change in Concept of CHD Treatment 33易损病人概念的提出Definition of Vulnerable PatientVulnerable plaques are not the only culprit factors. Vulnerable blood and vulnera

26、ble myocardium play an important role in for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death.“Vulnerable patient is proposed to define subjects susceptible to an acute coronary syndrome or sudden cardiac death based on plaque, blood, or myocardial vulnera

27、bility.Naghavi M. et al. Circulation 2003; 108(14):1664-72.易损病人=易损斑块+易损血液+易损心肌34 A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables listed below.Vulnerable plaques 易损斑块prone to rupture 易于破裂with high likelihood of thrombotic co

28、mplications and rapid progressionPlaque rupture accounts for nearly 70% of fatal AMI and/or sudden coronary deathsVulnerable plaque is the main, but not the unique cause for acute cardiovascular eventsVulnerable blood 易损血液prone to thrombosis 易于血栓形成Vulnerable myocardium 易损心肌prone to fatal arrhythmia

29、易发生致命性心律失常易损病人Vulnerable Patient35治疗上的创新性发展Development of Innovative Therapies脂质沉积 Lipid deposit调节血脂 Regulating Blood Lipid药物: 扩冠 Drugs：Nitrates, CaA手术 Surgery：PCI、CABG稳定斑块 Stabilizing Plaque, 抗炎 anti-inflammatory，抗栓(抗血小板、抗凝) Anti-thrombosis (anti-platelet,anticoagulation)早期识别；重预防 Early Identificati

30、on and Prevention冠脉狭窄 Coronary Stenosis易损斑块、破裂、血栓形成 Vulnerable Plaque, Rupture, Thrombosis易损患者 Vulnerable Patients36血脂康现代中药Xuezhikang Modern Chinese Herbal MedicineMaterial: special produced red yeast rice原料：特制红曲Method: red yeast rice (Oriza Sative L.) is grown on nutrient agar and special red yeast

31、 added, then fermented using modern biological technology to make the effective compound.方法：粳米加入培养液，接入特殊的红曲霉菌种，运用现代生物技术发酵而成。37ResultCARECCSPSTC-20%-13%LDL-C-28%-20%1st terminationNon-lethal AMI &CHD death-24% (P=0.003)-45%(P0.0001)Total CHD death-24%(P0.05）-33%(P=0.0003)CARE vs. CCSPS 38CCSPS亚组分析血脂康

32、广泛适用于特殊人群的调脂治疗合理积极谨慎老年人群高血压人群糖尿病人群39日本MEGA STUDY结果表明: 东方人群温和调脂即可明显获益,与CCSPS结果一致 MEGA Studys result : similar to CCSPS对日本人的一级预防: 服用10-20mg的pravastatin可使冠心病危险33%; 与美欧用20-40mg效益相当对轻中度Tc增高的东方人群低剂量是安全有效的Atheroscler Suppl. 2007 Aug;8(2):13-7. Epub 2007 Jun 22. LinksPrimary prevention of cardiovascular dis

33、eases among hypercholesterolemic Japanese with a low dose of pravastatin.Nakamura H; MEGA Study Group.Tokyo, Japan - Results of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study, the first large-scale primary-prevention trial in a Japanese populati

34、on that showed statin therapy reduces the risk of coronary heart disease (CHD), have now been published in the September 30, 2006 issue of the Lancet. MEGA, first presented by lead author Dr Haruo Nakamura (National Defense Medical College, Saitama, Japan) at the American Heart Association Scientifi

35、c (AHA) Sessions 2005 in Dallas, TX, showed that the addition of pravastatin 10 mg to a low-fat diet rich in omega-3 fatty acids reduces the risk of CHD in Japanese individuals with moderately elevated cholesterol levels by 33%, approximately the same reduction observed in US and European primary-pr

36、evention trials that have used larger statin doses.40Platelets are inflammatory cells血小板实乃炎症细胞41EBM 研究所得(Aspirin)Experience from EBM42抗血小板治疗的困惑Certain puzzled problem on anti-platelet therapy颅内出血胃肠道出血鼻腔出血胸膜腔出血皮下出血（aspirin 75-100mg/d, clopidogril 75mg/d) 高龄尤多见; 远超1.8-2.1（CURE 研究）可适当减量（包括首剂负荷量）43Aspir

37、in resistance概念的争议临床Aspirin resistance : 减少事件/未能消除事件 AA基因多态性/无效或不利结果生化Aspirin resistance : 出血时间延长/TXA2抑制合成/刺激血小板聚集 0.4-83.0% Dalen JE,et al:Am J Med,2007,120:1-4 Loordkipandize M,et al:Pharmaco Ther,2006,112:733-743 44川芎嗪抗血小板作用Anti-platelet Effects of LigustrazineThe active component of ABC herb-Lig

38、usticum Chuanxiong 活血化瘀药川芎主要成分Alkaloids 生物碱类 (Tetramethypyrazine, Ligustrazine)Lactones 内酯类 四甲基吡嗪Phenols 酚性化合物Ferulic acid 阿魏酸Others 其它45活血药抗TXA2生成Inhibitory Effects of ABC-herbs on TXA2 Production 46芎芍胶囊干预治疗研究XS0601 Reduces the Incidence of Restenosis Post-PCI (RIRE Trial, National Project)川芎有效部位 P

39、aeoniflorin赤芍有效部位 Chuanxingol(国家十五攻关课题) 安贞医院同仁医院中日友好医院西苑医院广东省中医院47临床研究流程 Survey of Study 335 cases enrolled 335例入选 Control group对照组 169 casesTreatment group治疗组 166 cases308 cases completed with 147 repeat angiography 308例完成试验，147例重复冠脉造影Randomized随机3 cases lost脱落12 cases exclude剔除3 cases lost脱落9 case

40、s exclude剔除154 cases154 cases(47.4%)48Comparison of clinical end-point event 两组临床终点事件的比较 Note: There was significant difference between the two groups(p0.05). Death 死亡0 0.00 00.00 Nonfatal MI 非致命性心梗1 0.64 10.64 Repeat PCI 重复介入治疗15 1.91 314.46 Event终点事件Treatment 治疗组Control 对照组 N (%) N (%) CABG 冠脉搭桥 0

41、0.00 30.00 干预PCI术后再狭窄临床结果比较 注: 两组比较有显著性差异(p0.05). 49 XS0601TreatmentStandard TreatmentP 0.05生存率比较XS0601 Improves Cumulative No-Event Survival50Integrative Medicine:The Experience from China结合医学经验：来自中国51 HS-CRP MCP-1 TNF- CD68 Control Dan Shen Chi Shao Chuan Xiong San Qi Jiu Da Huang Tao Ren CP Hs-CR

42、P: Hypersensitive C-reaction Protein; MCP-1: Monocyte Chemoattractant Protein; TNF- : Tumor Necrosis Factor-ABC+D药物对炎症指标变化比较Results: Inflammatory Marker Changes52 老年冠心病治疗多元模式Multiple Patterns for Elderly CHD Treatment优化药物治疗(证据和达标问题)PCI (Cypher/TAXUS,安全性/适应症的长期考察)CABG (搭桥与药物支架不能相互替代/在左主干和/或多支病变/或一支多处

43、病变/钙化比较严重的治疗中有优势)心理干预多元模式互补53心外膜冠脉开通心肌组织水平灌注冠心病治疗观念改变之四Fourth Change in Concept of CHD Treatment 54再灌注治疗是AMI治疗的里程碑，从被动、保守转为主动、积极的血运重建，挽救了无数患者的生命但临床发现， 约10-30%患者PCI成功后，心肌组织水平无再灌注，即无复流现象无复流是PCI后死亡和心梗的独立预测因素无复流现象的反思Asking in reply on no-flowFrederic SR, et al. Am Heart J 2003;145:42-46.55可能的机制Possible

44、mechanism可能的机制微血管结构完整性破坏微栓子栓塞白细胞聚集微血管功能完整性损伤，主要是痉挛所致血小板激活氧自由基56策略演变Strategic change 回顾再灌注历史：过去20年基本上是心外膜冠状动脉再灌注的20年，相信未来的10年将是微循环灌注的10年检测手段：冠脉微循环灌注评价：心肌声学造影成为热点防治手段：无复流防治：腺苷、CaA，活血化瘀中药等微循环改善剂：未来冠心病研究方向之一？ Diabetes Care 29:202206, 2006Circ J 2006; 70: 1099 1104)57一枝独秀三驾马车冠心病治疗观念改变之五Fifth Change in Co

45、ncept of CHD Treatment 58“药物支架时代”来临？ The trend of the DES times?DES的出现，使心血管介入技术向前迈进了一大步，成为冠心病介入治疗的第3个里程碑。BMS、冠脉搭桥术以及传统药物治疗是否真的要淡出舞台 59Stenting (including drug-eluting stents) reduces restenosis and repeated intervention, but does not reduce mortality or myocardial infarction. 支架不降低心脏病死率或心梗Serruys PW

46、, Kutryk MJB, Ong ATL. Coronary-artery stents. N Engl J Med 2006;354:483-495. 60FDA 05/12/2006 : 药物支架要求一万例验证三年FDA: Heart patients with drug-coated stents face blood-clot riskBy Associated PressTuesday, December 5, 2006 WASHINGTON - Patients implanted with drug-coated stents to hold open their choked

47、 arteries face a small but significant risk of blood clots, health officials said Tuesday, and a new study recommended they take clot-busting medications indefinitely. Growing concerns about the long-term safety of drug-coated stents comes to a head this week, when the Food and Drug Administration c

48、onvenes a two-day meeting to discuss clotting risks associated with the devices. In documents released Tuesday, the FDA said it is unknown whether there is an increased risk of death or heart attack in patients fitted with the so-called drug-eluting stents. However, those patients do face an increas

49、ed risk of blood clots a year or more after surgery compared with those fitted with bare-metal stents, the agency said in citing recent studies. Natick, Mass.-based Boston Scientific Corp. and New Brunswick, N.J.-based Johnson & Johnson are the only two companies approved to sell the drug-coated ver

50、sions. The FDA is seeking advice on a wide range of questions on the popular stents, including whether to update their labels with new warnings, identify patients for whom they arent appropriate and perhaps change federal recommendations on how long people should take blood thinners like Plavix and

51、aspirin following stent surgery. 61Stent vs CABG国际上正在组织三个大规模随机对照临床研究进行多支血管病的DES和CABG疗效评估，相信这些研究将有助于明确二者各自的优势和适应证。 FREDOOM:多支血管病合并糖尿病患者的DES和CABG的对比研究；SYNTAX:左主干和(或)多支血管病的DES和CABG对比研究；COMBAT:左主干和(或)多支血管病的DES和CABG的对比研究。62目前认识Understanding at presentDES总体是有较好效果的，但长期应用安全性仍有待大规模临床试验加以验证；DES术后更应强调坚持规范二联抗血小

52、板治疗，至少1年以上，以减少支架血栓的发生；大约6075%接受DES治疗的患者实际上并不一定需要DES，临床应严格掌握适应症；63Stent vs CABG在左主干和/或多支病变中，CABG有优势;在美国，只有18%的左主干和/或三支病变患者选择支架植入;在欧洲，在复杂病变血运重建中，CABG仍占有主导优势。64关注冠心病Hybrid技术Pay attention to Hybrid treatment冠心病杂交手术(Hybrid技术)： 联合应用介入治疗/搭桥手术, 优势互补,一站式完成 再血管化,是冠心病治 疗的重要发展方向。 65Life Wide Open开放生命66危险因素单一控制危

53、险因素复杂干预冠心病治疗观念改变之六Sixth Change in Concept of CHD Treatment 67DiabetesDyslipidemiaHypertensionObesity68多重危险因素的干预Interventions for multi-RF单一危险因素的治疗常可使病人心脑血管病危险下降20%30%，意味着还有70%80%的剩余危险需要降低 69Polypill:心脏病一/二级予防Polypill Approach for Class I & II Preventionof Cardiac Diseases组成:辛伐他汀40mg, ACEI(赖诺普利), 半量噻

54、嗪类利尿剂(或阿替洛尔25mg),低剂量阿司匹林,叶酸; Composition: Simvastatin 40mg, Lisinopril, half-dose Atenolol, low dose aspirin, folic acid (BMJ 2003; 326:1407, 1419, 1423, 1427)目标: 55岁以上使用,可降低心脑血管事件80%; Target: for those aged 55 or above, could lower cardiocerebral incidence by 80%争议: 激烈; Dispute: Fierce A strategy t

55、o reduce cardiovascular disease by more than 80%70Caduet二合一复方已在美作为新药临床应用Caduet Combines 2 Drugs in 1 Tabletas a New Drug has been Marketed in the USCompany: Pfizer ； 络加喜片Regulatory Status: Approved by FDA in January 2004Treatment: HBP/Angina/High cholesterolTablet Strengths(mg):Amiodipine (Novasc)/atrovastatin(Lipitor) = 2.5/10, 20, 40; 5/10, 20, 40, 80; 10/10, 20, 40, 80.(ASCOT trial,